Author: acflewis

First, let’s look at a paradigmatic example of a polygenic score publication. Inouye et al constructed a Polygenic Risk Score for CAD, gaining a hazard ratio of 4.17 for those in the top 20% compared to bottom 20% of their score. It is better as a single predictor (based on Area Under ROC curve, also known as C-statistic) than any one of smoking, diabetes, hypertension, body mass index, self-reported high cholesterol, and family history (it does not do as well as all of them put together). They conclude that their score “strengthens the concept of using genomic information to stratify individuals for CAD risk in general populations and demonstrates the potential for genomic screening in early life to complement conventional risk prediction.”

In reaction to articles such as this, several clear lines of criticism have emerged

The scores are only applicable in the ancestral population that they were developed in. Combine this with the well publicised fact that almost all studies are on Caucasian populations (reviewed here), and that the assays used are SNP chips whose genetic variants were chosen based on frequencies of variants within European populations, and several issues are immediately apparent. As an alternative to producing scores separately for each ancestral population, a suggestion that studies based on African populations would be less biased and more generalizable to other populations. It is based on the simple fact that non-African populations have been subject to more genetic drift – i.e. change in genetic variant frequency because of small population sizes. It is also the case that there are hazards aplenty in using differences between populations to infer anything about genetics, and particularly about natural selection (see g.g. this article).

Hazard ratios have to be very high to be useful as screening tools. In an article that has been well circulated on twitter, “The illusion of polygenic disease risk prediction”, the authors point out that “the paradox is largely explained by the fact that odds ratios or hazard ratios typically compare risks in the tails of a single risk distribution, but these ratios ignore the proportions of individuals who will or will not develop the disease that fall in the region between the tails of the distribution”. The first author, Nicholas Wald, has been pointing this out for a long time. Note that this does not just apply to genomics, in his 1999 paper Wald takes as its case study cholesterol levels for heart disease, and shows how poor a screening test this is. (They state that no future polygenic risk score will produce a high enough relative risk — it would be good to check this, based on a score that captured the full heritability estimates for a given trait.) This argument ought not to be news. I enjoyed this slide deck by epidemiologist Cecile Janssens that traces the history of the prospect of predictive genomic tests, and some of the known pitfalls.

The role of the environment means that genetics is often not as useful as these scores would suggest. If the environment changes, e.g. all people stop smoking, then the polygenic scores change too. If the genetics is mediated by an independently measurable and modifiable intermediate phenotype, e.g. cholesterol levels, then it is much less useful to know the genetics. Though see the Inouye paper showing that their score is relatively independent of other known risk factors.

The latest chapter on heritability, from a study of Aetna’s database of insurance claims covering about 45m individuals. Their dataset has over 56,000 pairs of twins born since 1985, and over 700,000 sibling pairs. They connect zipcodes to environmental factors of interest — SES, air pollution and weather/climate. They found that variance from these measures was much lower than from genetics and shared environment, with obesity being the phenotype with the strongest link to SES (var=0.027). Monthly cost of data was estimated at 29% heritable and 30% due to shared environment. The respective figures for co-morbidities were 43% and 24%.

The BabySeq project reports on results of exome sequencing of 159 newborns (127 healthy and 32 in the NICU). Of these 15 (9.4%) had genetic variants associated with a disease that could be managed in childhood. Genomic sequencing for newborns remains a contentious area.

An AP poll found 70% of Americans supportive of genetic editing “to prevent an incurable or fatal disease a child otherwise would inherit, such as cystic fibrosis or Huntington’s disease”, about two thirds to “prevent a child from inheriting a non-fatal condition such as blindness, and even to reduce the risk of diseases that might develop later in life, such as cancers”, and about 70% oppose “using gene editing to alter capabilities such as intelligence or athletic talent, and to alter physical features such as eye color or height.” I can’t find any original data, just reports e.g. here.

I thought this was an interesting story about how much of an impact the classification of a disease can make — in this case, the efforts to have schizophrenia classified as a brain disease so that it was covered by a new CDC program. Why does this matter? Mental conditions receive less funding and health insurance is often less generous. Strong echoes of dualism here.

The major news was the report of the birth of the first children genetically modified as embryos. I report on that separately here.

The question of whether those who receive a genetic diagnosis have a duty to tell their family members is working its way through the UK courts. A man who received a genetic diagnosis of Huntington’s asked the hospital not to tell his daughter, who was pregnant at the time, because he feared she would abort the baby. The daughter has since been found to have the genetic variant associated with Huntington’s is now suing the hospital. Bioethicist Anna Middleton told the Guardian “This could really change the way we do medicine, because it is about the duty that doctors have to share genetic test results with relatives and whether the duty exists in law.”

PsychENCODE, a large consortium looking at functional genomics in over 2000 developing and adult brains, has published 10 papers. To focus on one paper, they found that differences in gene expression between individuals are mostly explained by differences in fractions of cell types, and that some disorders and aging are associated with changes in these proportions. For schizophrenia, they found 321 genes associated with GWAS loci, and then did some fancy machine learning to predict phenotype from genotypes and from expression. This model did much better than a genotype polygenic score alone, and still did better when the expression data was imputed (i.e. not actually experimentally measured), “highlighting the value of having just a small amount of transcriptome data for disease prediction.”

Large study of the genetics of ADHD finds reproducible loci. A polygenic score predicts 5.5% of the variance (for an odds ratio of 1.56). The study presents evidence that ADHD should be considered the end of a distribution: “Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.”

A much smaller fraction of developmental disorders (DDs) are explained by recessive variation in protein-coding genes than previously thought: ~3.6% in non-consanguineous populations, compared to 31% in consanguineous populations. Compare to 50% of DDs caused by de novo mutations. This work, from Hilary Martin et al appearing in Science, is based on a burden analysis approach in over 6000 exomes from the Deciphering Developmental Disorders study. “The high proportion of unexplained patients even amongst those with affected siblings or high consanguinity suggests that future studies should investigate a wide range of modes of inheritance including oligogenic and polygenic inheritance as well as noncoding recessive variants.”

“Just thinking you have poor endurance genes changes your body” – individuals were told a test had revealed they had one or another version of the gene CREB1, which affects how easily one tires, and were then set to run on a treadmill. Those who were told they had the version would meant they would tire more easily did indeed tire more easily. In fact, the participants had been randomized. Likewise for FTO, which can affect how full you feel, participants who were told they had the “less hungry” version of the gene reported feeling less hungry, and had higher levels of a hormone associated with feeling full. This would be a type of placebo effect for genetic information: “The results suggest that if a person just thinks they are at high risk for, say, obesity, it could change their physiology in a way that makes them more prone to the condition, Turnwald says.” (Paper here). “If simply conveying genetic risk information can alter actual risk, clinicians and ethicists should wrestle with appropriate thresholds for when revealing genetic risk is warranted.”

Calico and Ancestry.com have teamed up to show that longevity is <10% genetic. Using a single pedigree of over 400 million individuals, they were able to show that previous estimates (about 15-30%) overestimated genetic inheritance because they were confounded by non-genetic inheritance showing up via the effects of assortative mating.

We’ve known for a long time that there is a lot of undiscovered genetic diversity in African populations, and that use of the reference genome is rife with problems. Sequencing of 910 African genomes has showed just how large the problem is: at least 10% of reads failed to align to the reference genome, but were alignable to constructed pan-African contigs.

Mendelian Randomization is the idea that because genetics at birth is randomized and not altered by environmental confounders, considering some gene X, one can see whether gene X is subject to Loss or Gain of Function variants in the disease of interest. If it is, then Gene X is s good drug candidate – many high cost drug trials could have been avoided if MR had been performed. The technique can also be used to distinguish between correlation and causation, for example in showing that the correlation between obesity and depression is at least partially explained by obesity causing depression (depression odds ratio of 1.18 for 1 SD higher genetic risk score for high BMI). There are many improvements to the most basic MR model, see e.g. correcting for genetic correlations with shared etiology.

A study has shown that over 30% of patients had their variants reclassified within a five year time period. “The findings of this study suggest that pediatric patients with epilepsy and previous genomic test results should have their test results reinterpreted at least every 2 years and before further genetic testing.”

More calls for a universal DNA database for use in forensics: “if correctly implemented, a universal database would likely be more productive and less discriminatory than our current system, without compromising as much privacy.”

The UN’s Convention on Biological Diversity considered, and rejected, a ban on gene drives. Both those working on gene drive technology and those campaigning against it called the result a win. They state the need for informed consent, but it is not clear what this means: “who gets to decide when the African people have consented — and how unanimous a decision you need when millions of lives are on the line”

In April 2018 the FDA issued guidance on the use of databases in genomic testing. Applying that guidance, they have approved use of ClinGen’s Expert Curated Human Genetic Data as clinical evidence in approval submissions for tests. The data covers over 10,000 variants (ClinVar review status (“reviewed by expert panel”or “practice guideline”).

I first learnt about Lulu and Nana by watching the video that Chinese scientist He Jiankiu published explaining why he had edited embryos leading to the births of the first genetically modified babies. This is strongly recommended viewing. You can read the story, as broken by the AP, here. His claims have yet to be verified.

It was anticipated that the first International Summit on Human Gene Editing, held three years ago, would result in a consensus statement calling for a moratorium on genetically modified babies. There was no call for a moratorium. Since then, others have failed to call for a moratorium. Including the US’s National Academies report (which I covered here) which instead produced a checklist for when editing could be performed (p132), and the UK’s Nuffield Council report.

There has been much criticism of He, for example Oxford’s Julian Savulescu, famous for arguing that we have a moral imperative to have the best children possible, described the work as “monstrous”; Penn’s Dr Kiran Musunuru described it as “unconscionable” (link). These voices included Chinese: Qiu Renzong, bioethicist and emeritus professor at the Chinese Academy of Social Science in Beijing, stated that the work was clearly not ethical, and a fraud (link).

While most have strongly condemned He’s work, some have taken a less accusatory stance. At the summit, Dr. George Daley, dean of Harvard Medical School, characterized He’s work as a “misstep” and argues “It is time to move forward from [debates about] ethical permissibility to outline the path to clinical translation … in order to bring this technology forward.” (link). George Church states “I feel an obligation to be balanced.”, calling the criticisms of He bullying.

Should the scientific community have acted differently? David Baltimore, the convener of the Second Summit, (reported by STAT) states that “I think there has been a failure of self-regulation by the scientific community because of the lack of transparency.” Scott Gottlieb, FDA Commissioner, goes further and says that the scientific community should not have given He a platform to self promote his work. “The response from the scientific community has been far too slow and far too tepid, and the credibility of the community to self-police has already been damaged… Governments will now have to react, and that reaction may have to take consideration of the fact that the scientific community failed to convincingly assert, in this case, that certain conduct must simply be judged as over the line” (reported in BioCentury). The work would have been illegal in the US. It also likely contravened Chinese laws (link). Lawyer Glenn Cohen questions that there could be a complicit scientific community, “it seems to me that the community is acting exactly as it should when one of its members breaks the covenant” (link).

The details of the research help highlight some open ethical issues. The aim of this research was to disable the CCR5 gene, a mutation that some people (though not Han Chinese) naturally have that is protective against HIV infection. The choice seems motivated to be a CRISPR first, rather than a pressing therapeutic need. Disabling a gene is much easier than precisely tweaking a “broken” gene to be functional. The desire for fame, to have a first, was a clear motivating factor for the research: the team wrote in their submitted ethics statement “In this ever more competitive global pursuit of applications for gene editing, we hope to be a stand-out”. Potential parents were only eligible for the study if the father had HIV. Infertile women are not eligible for IVF if their partner has HIV (link). The research is thus particularly question worthy as it a) blurred the lines between research, which is supposed to recruit individuals whose main aim is to contribute to scientific knowledge, and clinical application, where direct benefit is expected, b) edited healthy embryos, rather than seeking to “fix” those who would otherwise go on to develop a serious condition, c) individuals with the introduced edit have a higher chance of infection with the West Nile virus, and a higher chance of dying from influenza; as a protective mutation, d) the edit blurs the enhancement/therapy line, e) one of the embryos was known heterozygous (and hence would not have had the protective benefits) pre-implantation; whether the prospective parents could give true informed consent has been questioned. For the very real risk of off target effects, the consent form stated that “the project team is not responsible for the risk.” The case highlights just how ambiguous language is: An item on NASAM’s checklist was that editing be done for an “unmet” medical need. As Church points out, there is no cure or vaccine for HIV. On the other hand, HIV is both preventable and treatable.

What happens next? There are decisions ahead for any editor who receives the work to review. Francis Collins, who heads the NIH, has called for a “binding international consensus”. An editorial in Nature calls for a global registry of work genetically modifying human embryos. Carl Zimmer, writing in the New York Times, draws the parallel to babies born via mitochondrial replacement therapy, and the example of how the UK has made this legal within a highly regulated environment. Throughout this debacle, two reference cases have been given. The first is to Louise Brown, the first baby born by IVF. In the years around her birth, public opinion changed from being opposed to interfering with nature in this way, to being supportive of IVF (see Table 2 here). The second is to Jesse Gelsinger, who died in 1999 after receiving an experimental gene therapy. His death seems largely creditable to hastiness around excitement of a new technology. As George Church states, it is too early to tell whether Lulu and Nana will be Louise Browns or Jesse Gelsingers. But note that, post Jesse’s death, gene therapy is once again being pursued with gusto.

Why China? While international science incentives “firsts”, this may be acutely felt in China. As Jing-Bao Nie argues, “China’s science schemes have much to do with the developing mentality that ethics is merely secondary and instrumental for cutting-edge scientific investigation and technological invention”. Additionally, Chinese society places less emphasis on the individual: As Antonio Regalado reports here, “A person who knows He said his scientific ambitions appear to be in line with prevailing social attitudes in China, including the idea that the larger communal good transcends individual ethics and even international guidelines.” Indeed, He commissioned an opinion poll that found majority support of the Chinese public for therapeutic genetic modification (this is inline with polls in the US).

I think we will see public acceptance of genetic modification of embryos, first in the therapeutic setting, and probably first in a country such as China. As we have learnt time and again from the Assisted Reproductive Technologies space, technology does change morals.

I continue to struggle to find a format for these round-ups. I am finding the division Science/Applications/Regulation useful, but there a few stories that never quite fit that pattern. I realized that these are mostly the controversial ones, and so I have carved off a section dedicated to the eyebrow raising.

Nature News reports on the The approach to predictive medicine that is taking genomics research by storm. One of the leading scientists behind polygenic scores, Peter Visscher, a geneticist at the University of Queensland, states that “I’m absolutely convinced this is going to come sooner than we think.” Myriad has begun including a polygenic score for breast cancer on its reports, in something that is rather convenient for sales, “One of the strengths of these scores is that they provide a result for everyone, says Jerry Lanchbury, Myriad’s chief scientific officer.”

Genomic Prediction launched their Expanded Pre-implantation Genomic Testing in September. It covers many single gene disorders and uses polygenic scoring for complex disorders (Type 1 Diabetes, Type 2 Diabetes, Coronary Artery Disease, Atrial Fibrillation, Breast Cancer, Hypothyroidism, Mental Disability, Idiopathic Short Stature, Inflammatory Bowel Disease). They are working on height. The cost will be $400 per embryo (source). From the same source, the CSO, who has Type 1 Diabetes, explains that the company wants to move on to genome editing “If his own parents had that option, “they could have potentially edited out my diabetes and it would have been a cure,” he said. “I would have been here without diabetes.” The irony is, if his parents had access to their PGD product, he would probably never have been born.

In a striking example of the misuse of genetics, an image of white supremacists chugging milk has been doing the rounds. The act goes with the message that those who can’t digest milk should “go home”. Those of caucasian ancestry, and inconveniently for the supremacists, also those of East-African ancestry, tend to have the ability to digest lactose. The report by Amy Harmon in the NYT states plainly some of the problems with addressing this: “Many geneticists at the top of their field say they do not have the ability to communicate to a general audience on such a complicated and fraught topic. Some suggest journalists might take up the task. Several declined to speak on the record for this article. And with much still unknown, some scientists worry that rebutting basic misconceptions without being able to provide definitive answers could do more harm than good. “There are often many layers of uncertainties in our findings,” said Anna Di Rienzo, a human genetics professor at the University of Chicago. “Being able to communicate that level of uncertainty to a public that often just sees things in black and white is very, very difficult.” The ASHG released a statement condemning this use of genetics, saying that concept of “racial purity” was scientifically meaningless.

Robert Plomin’s book Blueprint, which is newly released in the UK, is already stirring controversy. One commentator notes “Yet in the end with Blueprint, there exists a risk that readers end up impressed by Plomin’s account of his science without being aware of the racial and social implications of his theory. And in the context of a resurgent right wing across the world looking for “scientific” reasons to elevate race in public policy, this seems profoundly irresponsible.”

Science

The UK biobank has released its data on 500,000 individuals. Each individual is genotyped, and will have their health outcomes collected prospectively. MRI data for 100,000 of the individuals should be available by 2020. “UK Biobank is an open-access resource that encourages researchers from around the world, including those from the academic, charity, public and commercial sectors, to access the data for any health-related research that is in the public interest.”

In further results reported ahead of publication at ASHG, in a dataset of ~490,000 people researchers identified 4 variants (2 just in males) that are associated with having had same-sex partners, a trait that is about ~40% heritable. “We found that variants predisposing to non-heterosexual behavior are, among heterosexuals, positively associated with having more self-reported lifetime sexual partners and, in heterosexual males, with being judged more to be physically attractive. This is consistent with the hypothesis that genetic variants predisposing to non-heterosexual behavior confer a mating advantage to heterosexual carriers.”

Continuing the story of the widely covered Educational Achievement polygenic score which I covered in my last post

Economic researchers applied the score in combination with economic data (working paper). The results? As one of the authors reported to the Post, “If you don’t have the family resources, even the bright kids — the kids who are naturally gifted — are going to have to face uphill battles.”

A twin study based on UK individuals on the genetics of university success produced heritability estimates for: entrance exam achievement (57%), the choice to study at university (51%), the quality of university attended (57%) and achievement at university (46%). (Numbers are the proportion of variance in the trait explained by inherited factors). The Educational Achievement polygenic score, which captures 11-13% of variance in number of years of education, captured 4%, 5%, 2%, 7% of this variation respectively.

This was a piece I started to read not expecting a connection to genomics: the story of the placebo effect, and attempts to unpick its biochemistry. Researchers formed a hypothesis that variation that affected the levels of COMT, an enzyme that helps determine levels of dopamine and its relatives. They have indeed found evidence of this. The suggestion is that somehow the caring involved in a patient-physician interaction stimulates the same biochemical pathway that many drugs use. This suggests that the blinded placebo trial may be inappropriate: “the placebo effect is not just some constant to be subtracted from the drug effect but an intrinsic part of a complex interaction among genes, drugs and mind.” And of course “The [pharma]industry would be delighted if it were able to identify placebo responders — say, by their genome — and exclude them from clinical trials.” Thinking beyond trials to the administration of medicine, “Should medical rituals be doled out according to genotype, with warmth and caring withheld in order to clear the way for the drugs?”

I had previously missed this: a European initiative to overcome data silos and privacy concerns to assemble a million genomes by 2022.

A new study from Calico and Ancestry.com estimates the heritability of lifespan to be under 10%. It was previously believed to be higher, but they think that this was inflated due to the effects of assortative mating.

The largest ever genetic study from China of over 140,000 Chinese individuals has been reported. It was based on blood processed for Non-invasive prenatal testing of pregnant women.

Gout was previously thought to be associated with diet. But a new study of ~17,000 individuals finds that the effects of diet are very minimal, whereas genetics plays a large role, explaining ~24% of the variance.

It’s easy to bash precision medicine, but there are some success stories. Here’s a story of a N-of-1 drug for a girl with Batten disease, which is fatal. The drug is an antisense oligonucleotide, the same class of drugs as nusinersen/Spinraza for spinal muscular atrophy (SMA)

The BabySeq and MedSeq projects, with both sequence genomes of healthy individuals, reported at ASHG that they had found “unanticipated risk variants” in 16 of 110 adults (14.5%) and 18 of 159 infants (11.3%). Upon follow up, some of these were found to indeed have the diseases indicated. These numbers were higher than they were expected.

A comparison of data sharing regulations in seven countries. Part of the Global Alliance for Global Health, the work was seen as a prerequisite to build upon: “The future of genomic data sharing depends on a creative yet responsible interpretation of existing legal norms in order to ensure that we truly respect the human right of everyone to benefit from scientific progress and its applications,” said Knoppers.

A meta-analyses of studies investigating people’s fears of genetic privacy found over 50 studies, found “The picture of genetic privacy that emerges from this systematic literature review is complex and riddled with gaps.” I found this conversation with Jen King, director of consumer privacy at the Center for Internet and Society at Stanford Law School, referencing results that people tend not to think of their genetic data as any more personal than their google searches. This motivates contributing data to research, but individuals can think differently again when they are walked through potential implications — e.g. that drug companies can sell any drugs produced at whatever price the market will bear.

A major theme that emerges for me over the past few months is on non-medical uses of genetics, made possible by 1) Continued growth of Direct to Consumer (DTC) testing, 2) large scale studies of non-health traits, and 3) increased acceptance of polygenic risk scores, whereby an aggregate score for a given trait is made from small contributions from many genetic markers. This is something we need to talk about.

1) Millions of DTC tests have been sold in the US (over 12 million, according to one estimate from February). A poll found that “Some 17 percent of Americans already have undergone at least one kind of DNA test, and 52 percent of the remainder say they’d like to.”

2) In the last few months, there have been large scale studies of neuroticism, intelligence, social mobility, and on social traits including loneliness. A lot of research into such “social” traits is performed under a health mandate, as many such traits correlate with health outcomes.

3) Polygenic risk scores can be much better at identifying those at risk of serious conditions. That’s the conclusion of a paper and the basis for a new tool that will ingest e.g. 23andMe data and give you a score. From the paper: “The approach identifies 8.0, 6.1, 3.5, 3.2, and 1.5% of the population at greater than threefold increased risk for coronary artery disease, atrial fibrillation, type 2 diabetes, inflammatory bowel disease, and breast cancer, respectively.” These successes, combined with the type of studies I listed above, lead to, for example, educational achievement and cognitive performance polygenic risk scores, explaining 11-13% of variance, 7-10% of variance respectively. Such scores have already make it into DTC tests, for example educational achievement markers are available from Helix.

Needless to say, such scores have the potential for large social implications. The educational achievement study has appeared all over the press, but I have found good critique of possible implications scant. This piece is an exception, one example:

“There’s as much to be learned about the nature of our educational system as about the nature of the individual in this data,” said Mary Helen Immordino-Yang, professor of education, psychology, and neuroscience at the University of Southern California. Specifically, if certain genetic variants are associated with better educational outcomes, then there might be something about the structure of our educational system that’s favoring people with these variants. For example, if the variants were involved in language comprehension, that could tell educators that current teaching methods aren’t working for students who process language differently. That means they should be designing new interventions to accommodate that variation, Belsky said.”

In the light of Ancestry.com and Spotify teaming up to offer playlists based on your results, a critique of how genetic ancestry testing, who focus on the fact your DNA reveals something meaningful about you. This runs from “conflating DNA and cultural identity” (routing for a World Cup team based on results) to “game programs set up to address past injustices” (using results to prove Native American or African ancestry), to reifying race as a meaningful category (citing a study that showed reading about these tests increased beliefs in racial differences).

I think it is worth highlighting what we have learnt about consumer preferences

The Associated Press reports a poll of 1109 adults it performed on questions related to genetic testing (also refed above on number of people interested in genetic testing). On whether people would want to know if DNA showed they had a genetic variant associated with an incurable disease. 60% said Yes, for under 30s the number was 78%. Most (but not all) would tell family members). The poll also asked about the use of DNA by the Feds — “Half of people think genetic data should be used to help solve crimes only with the consent of the person tested, a third think it’s OK without that consent — and 13 percent don’t think law enforcement should use it at all.”

A Pew poll found majority support for gene editing for babies for health reasons. Men and more supportive; religious people are less supportive. If the intervention relies on testing embryos, most are opposed.

A U of Michigan study on patient attitudes to their biobank samples being commercialized. “67 percent of participants agreed that clear notification of potential commercialization of biospecimens is warranted, but only 23 percent were comfortable with such use. Sixty-two percent believed that profits should be used only to support future research, and 41 percent supported sharing profits with the public.”

STAT reports on consumer adoption of genetics in China. Those in the space refer to a particular emphasis on a Chinese fascination of how genetics affects identity and destiny, and, for the generations born under the one child policy, with finding family. Routine newborn genome sequencing is on the cards within the next five years (Veritas already has a product in pilot out there). Because there isn’t an entrenched medical genetics profession, there will be less paternalism about results.

It strikes me that the academic literature is all about efforts to ensure that people’s informed choices are respected. A lot of this type of work, which looks at what those choices are likely to be, happens outside the academic mainstream. This is an observation I intend to check.

A NYTimes Op-Ed that successes of precision medicine and vastly outnumbered by failures. At the ASCO conference, the four precision therapy trials presented with results were all failures, and yet there was no news reporting.

Federal money to develop a system intended to recognize emerging bio threats based on DNA orders placed, to e.g. spot if someone was trying to re-create an extinct virus.

Regulation

An extension to the European Convention on Human Rights and Biomedicine covering genetic tests come into force on July 1, ten years after it was written. It covers “Article 3 – Primacy of the human being: The interests and welfare of the human being concerned by genetic tests covered by this Protocol shall prevail over the sole interest of society or science, ” and bans genetic discrimination. It outlines the procedures involved if a person is not able to give consent, and clarifies that the information from a test should be made available to the person.

A four year effort has culminated in a recommendation not to sequence all newborns, published by the Hastings Center in the context of a whole issue dedicated to investigating the ethics of the issue. Meanwhile, the four year BabySeq project reports a low uptake in the study by parents of newborns — only 10% were interested in an enrollment session, of whom 67% signed up.

Gene therapy trials have traditionally requires an additional layer of oversight, provided by the Recombinant DNA Advisory Committee (RAC). But that special treatment will no longer needed. Gottlieb and NIH Director Francis Collins wrote “there is no longer sufficient evidence to claim that the risks of gene therapy are entirely unique and unpredictable—or that the field still requires special oversight that falls outside our existing framework for ensuring safety.”

In the 1970s, scientists converged on a “14 day rule”: embryos could be studied up to 14 days post fertilization, which is when the “first inklings” of a nervous system first appear, and the point at which the embryo can no longer split. At that time, it wasn’t possible to keep embryos alive in cell culture beyond a few days. Now, scientists are just about at the 14 day limit. To push beyond this limit, some researchers have used “synthetic embryo like structures” made from stem-cells. This piece covers the advances.

Gene drives in mammals reported for the first time — the inheritance of a specific genetic variant went from 50% to 73% in female embryos only, suggesting the controversial tech has a long way to go. (Note that gene drive research in mosquitos is being actively pursued.)

A case of uniparental diploidy, where most of an 11 year old’s cells only have DNA from her father. She has not yet presented malignancy, though all of the other ~20 such cases worldwide have presented malignancy early in life.

An accessible introduction to “Inborn errors of immunity” — where genetics, rather than unspecified bad luck, can lead to someone succumbing to an infection. Knowledge of the underlying genetics can lead to successful therapeutic approaches.

A tool to predict how many SNPs, and hence what sample sizes, are likely to be involved in various traits.

Knowledge of how genetics influences behavior can lead to “free will doubt”, with potential implications for how individuals view justice. In general, free will doubt decreases support for justice based on retribution, towards justice based on consequentialism. A study shows that, while this is true for violent crime, for “low affect” crime, free will doubt actually decreases support for either type of justice.

The genome can gather mutations as we go through life (a phenomena well known as the cause of cancer). A study (and a nice write-up) shows that early life experiences can end up written in your DNA — some genetic mutations in brain cells depend on the amount of maternal care baby mice received.

And finally, a nice piece from science historian Oren Harman on use of the term “gene” — historically and in the future. And another lovely piece about how some of the genes got their names, including the background to “Pray for Elves”, which I learnt originates with someone I used to work with, Prof Mark Yandell.

Well, an embarrassing amount of time has passed since I posted last. I am on the road in South America, but was feeling increasingly angsty about being behind on genomics happenings. So I have spent the last three days catching up. Here is my pick of the most interesting developments:

Close to society

The Golden State Killer left DNA behind at many of his crime scenes from 1974-86. The DNA did not lead to any suspect until April of this year, when an officer uploaded the killer’s genetic profile to an open source genetic database designed to help people find relatives. They got a partial hit to a family member, and used this to identify a suspect subsequently found to be a match to the killer. The same technique has been used for other cases. I will write much more extensively about this case separately.

The All of Us program has officially launched(formerly the Precision Medicine Initiative). The project aims to enroll 1 million US residents, and anyone over the age of 18 can sign up. The first interview question Scientific American asked the program’s director Eric Dishman was about the golden state killer case, the response was that law forbids one federal agency sharing data from the program with another, even if subpoenaed. A moving story from WIRED about some of the individuals behind the diversity programs for the project.

Dubai Health Authority(DHA) is planning to map the genomes of all of its residents. It aims to“issue reports that support research, forecast future disorders and epidemics, and plan preventive measures.”

In a startling combination of buzz words, there is a plan to publish the cannabis genome to a blockchain, as a challenge to the conventional scientific publishing market. The idea is that this model will give a permanent, transparent record of a scientific advance, preventing corporations from laying claim to certain advances.

The EarthBioGenome project(EBP), which aims to sequence the ~1.5 million known eukaryotic species in the next 10 years, is facing up to some of its challenges, including finding funding for the endeavor, which has an estimated price tag of ~$5b.

It has long been argued whether knowing information about genetic risk actually improves health outcomes by altering behavior. A new study using risk score for cardiac health risks did find changes in behavior.

New science

More on the somatic genome: we all have pieces of circular DNA, formed from breakpoints.

In a new chapter for how nurture can shape nature, the not so static genome: How attentive a mother is to her babes correlates with how many copies of the jumping gene L1 the babies have.

In another contribution to the nature-nurture debate, genetic risk for schizophrenia is modulated by the placental environment – schizophrenia patients who had these early life complications(ELCs) had higher polygenic risk scores, and the genetic scores better predicted schizophrenia presence in individuals with ELCs. The genes involved are expressed in the placenta during complicated pregnancies, signalling a placenta under stress.

A role for pericentromic Satellite DNA, part of the non-coding DNA previously without a known function, has been shown to be vital in holding the genome together in the nucleus, through a protein called D1 that binds to it and helps hold chromosomes together.

And more work that highlights the role of rare variants, from a study that uses a large cohort of de-identified EHR data and genetic data to identify patients who have symptoms associated with rare genetic diseases, to try and identify those who may have an identified genetic condition, and then looking for common underlying genetics of those identified.

Genetic modification

“Genome surgery is coming”, says the team that reports the first successful results of find-and-replace CRISPRing of a heterozygous mutation causing in a retinal disease. The challenge in these autosomal conditions is to just target the faulty version.

CRISPRing cells can activate the cell’s DNA repair mechanism pathways, specifically that involving p53. This can cause a selective advantage for cells that have a compromised p53 pathway, i.e. CRISPR can lead to a selective advantage for cancerous cells. The conclusion“p53 function should be monitored when developing cell-based therapies utilizing CRISPR–Cas9”.

Spotlight on genetics and intelligence

Pedigree-based analysis, in particular twin based studies, give us estimates that variance in intelligence is about 50-80% inherited. Previous work in genetics had not identified much of this variance(for intelligence and all other complex traits), leading to a“heritability gap”. A study of over 20,000 individuals, many from the same families, who had been SNP genotyped at 700,000 locations claims it can explain about 54% of the variance in general intelligence with genetics, substantially closing the heritability gap. They were able to close the gap through assessing the contribution of rarer variants, finding that variants with a frequency less than 1% contribute 23% of the variance. It looks like prior genotype based work missed causal variants in low linkage disequilibrium with genotyped SNPs — variants they were able to find because of the related individuals in their dataset.

One might wonder, why bother studying the genetics of intelligence? The justification given by these papers is through the fact that intelligence correlates with health outcomes, and so a better understanding could lead to better health outcomes.

Spotlight on genetics and race

And finally, an op-ed by Harvard geneticist David Reich titled“How Genetics Is Changing Our Understanding of‘Race’” has stirred up an old can of worms, by claiming that political correctness is stifling science by refusing to acknowledge genetic differences between the“races”. The likes of Sam Harris have jumped on the bandwagon. The sentence“But as a geneticist I also know that it is simply no longer possible to ignore average genetic differences among‘races.’” is the most controversial(in the book that the op-ed is mostly taken from, the same sentence uses the term“populations”). Here is an extract from an open letter that drives home the difference between races and populations:“In short, there is a difference between finding genetic differences between individuals and constructing genetic differences across groups by making conscious choices about which types of group matter for your purposes. These sorts of groups do not exist“in nature.” They are made by human choice. This is not to say that such groups have no biological attributes in common. Rather, it is to say that the meaning and significance of the groups is produced through social interventions.” Its clear how socially constructed of a term“race” has been, particularly in the US, where e.g. a single black ancestor would make you“black” under the one-drop rule. Many of Reich’s points would stand if he stuck to the terms“ancestry” or“population”. Possibly even the point that the proximity between ancestral populations and race makes some scientists timid in their explorations and communications.

(The whole debate reminds me that race, when gathered in scientific studies, is always self-reported, and hence any links to biology are very suspect. This point has been made by bioethicists in connection with the FDA’s approval of the drug BiDil just for those who identify as black.)

Hot topics over the past few weeks have included genetic privacy, blockchain-genetics start-ups, reimbursement. There have also been some surprising new science.

Ethical, Social, Legal

A“blackhole of accountability” regarding research participants. A privately funded, off shore, unregulated trial of a herpes vaccine has highlighted the lack of protections for research subjects in the US. Federal agencies are underfunded and have shown themselves to be unwilling to engage in even the most egregious cases. Bioethicist Arthur Caplan asks.“How is the government going to manage subjects, researchers and investors who don’t like regulations?”

A perspective from Laura Hercher on”the ghettoization of genetic disease”– that non-invasive prenatal screening will mean reduced prevalence of conditions such as Downs, but only in specific communities, as communities have very different cultural attitudes and access to abortion and to disability. We need a“genetics community that fights for all vulnerable individuals with as much vigor as it fights for reproductive rights.”

An argument for the importance of ethnic diversity in genomic datasets, from the point of view of access to genetic testing in the first place. And a genetic counsellors report that the saying“De algo nos vamos a morir”—“We’re all going to die of something is common from the hispanic population, and is an attitude that affects take up of genetic testing.

The right-to-try legislation, which passed in the Senate, has stalled in the House. Proponents argue that patients have the right to try any drugs that have been tested in humans. Opponents argue that the bill would undermine patient safety.

An interesting historical summary of the attitude of African Americans to eugenics in the 20th century argues that there was initially some enthusiasm for the prospect of racial improvement, but that disproportionate targeting of African Americans for eugenic legislation(such as forced sterilizations) changed this tide.

Adoption

A California rep has introduced a Federal bill designed to promote precision medicine, called the Advancing Access to Precision Medicine Act. The Act has been referred to the House Committee on Energy and Commerce.

Three of the top five articles of 2017 on Genomeweb concerned regulatory decisions, including FDA guidance around development of companion diagnostics in precision medicine, a Supreme Court decision regarding a decision concerning a forensic DNA kit, and FDA approval for a multi-gene, multi-drug companion diagnostic.

Last year CMS announced its coverage position for somatic genetic tests, which is basically to pay for FDA approved assays, which some have argued goes too far and others not far enough. Some commercial payors have indicated that they will likely follow suit.

Concerns around ownership of genetic data, in a world where anybody who gathers data knows that it has value and hence is reluctant to share it.

Genetic privacy hit the news again, with Senate Minority Leader Chuck Schumer called on the Federal Trade Commission to launch an investigation into the way DTC genetic testing companies handle customer data. He doesn’t think that companies should be able to sell individuals’ genetic data without their knowledge. The data can be subpoenaed in court, stolen, bundled and sold.

The first case of theft of the genetic information in DNA is in progress. It differs from previous cases in its focus on information rather than sample, and privacy rather than economic gain. So far, legal precedent is that you don’t own your DNA— which runs counter to the belief that many people have.

A commentary that outlines the tension between HIPAA’s requirement that individuals have access to their own data with FDA and CMS, who often regulate to limit access on the basis of safety concerns.

The UK Personal Genomics Project are putting together an“open consent”, based on the idea that whoever has had their genome sequenced is the final owner of the data

Products and Projects

Launch of Pheramor, a Dating App that incorporates DNA analysis of pheromone variability to help suggest potential dates. Based on science such as the sweaty T-shirt study, showing that we tend to be attracted to people with different HLA types than us, it is almost certainly an example of a little science being used to attempt something in a lucrative market.

23andMe have launched a weight loss study, designed to be both interventional and remote, timed for the New Year. They hope to involve 100,000 people. I signed up, and have been disappointed that all I have received from them with some minimal information about what foods to try and eat less of. They hope to gather data that will allow them to make tailored weight loss plans for their customers, and also to prove a model for running trials that could prove lucrative.

Couples can have carrier screening to determine what recessive diseases a child of theirs has a chance of having. HumanCode, for $259, uses the same techniques to look at the sunnier side of what a future child might look like, for example, whether they are likely to have a sweet tooth. Queue worries about labelling children, in this case before they are even conceived.

The Earth BioGenome Project and the Earth Bank of Codes have announced a partnership as part of the mission to sequence all 1.5 million vertebrate species and make their genomes available to those developing solutions to preserve biodiversity and promote sustainability.

Towards the holy grail in cancer diagnostics— an early detection test. A multi-institution effort called CancerSEEK based on cell-free DNA reports ~70% sensitivity and ~99% specificity.

An update from ClinVar, the public repo of variant classifications, most from clinical labs: there are now classifications on ~376,000 variants, covered by 582,000 submissions from ~900 submitters. Medically relevant discordance of classification is ~2%.

Block chain based companies, that will store your DNA and allow you to sell it to pharma companies:

Advances in nudging the micromiobe, through interfering with the metabolism of bacteria that are most abnormal in IBD.

Two papers(here and here) in Science identify which tumors are most likely to respond to immunotherapy— those with inactivating mutations in proteins involved in chromatin remodellin

A large fraction of people will likely have immune systems that attack Cas9, the main protein involved in CRISPR treatements. It is not surprising that many people have antibodies against Cas9, as it is a protein from a common bacteria. It is likely this finding won’t prove too much of an issue, as other versions of CRISPR use different proteins.

Basket trials, which try targeted therapies on cancer types other than those they are currently indicated for, are finding mixed results: these drugs do sometimes work in other cancers, but not all the time.